Work in the chick visual system has suggested that the graded expression of Repulsive Guidance Molecule (RGM) gene product might play a role in the establishment of topographic projections in the developing visual system from the retina to the tectum (Monnier et al. (2002), Nature 419:392-395). It has also been demonstrated Niederkofler et al. (2004), J. Neuroscience 24:808-818) that in the mouse there are three proteins homologous to the chick RGM (“cRGM”). The mouse RGM (mRGM) family members were named mRGMa: Genbank Accession number AI118914; mRGMb: Genbank Accession number BG519283; mRGMc: Genbank Accession number AA656608. Gene targeting studies in the mouse have shown that mRGMa does not appear to be involved in anterior-posterior mapping of topographic projections from the retina to the superior colliculus in the mouse visual system (Niederkofler et al. (2004), J. Neuroscience 24:808-818). Human homologues for all three genes have also been found (Genbank Accession numbers: huRGMa: NM—020211; huRGMb: NM—173670; huRGMc: NM—213653). By gene linkage analysis, the human RGMc has recently been demonstrated to be HFE2 (Papanikolaou et al. (2004), Nat Genet. 36:77-82). Based on linkage analysis, a role for the RGMc/HFE2 gene in the regulation of iron metabolism in humans has recently been proposed (Papanikolaou et al. (2004), Nat Genet. 36:77-82). Tissue profile experiments demonstrated expression of mRGMc predominately in muscle, with highest levels in skeletal muscle, as well as heart and liver (Niederkofler et al. (2004), J. Neuroscience 24:808-818).
Human juvenile hemochromatosis is an early-onset, autosomal recessive disorder of iron metabolism resulting in increased iron absorption and storage. This iron overload has been associated with cardiomyopathy, diabetes and hypogonadism presenting in the teens and early 20s. Recently, mutation of HFE2 on chromosome 1q has been shown to cause this disease in humans (Papanikolaou et al. (2004), Nat Genet, 36:77-82). Human HFE2 encodes the protein hemojuvelin, which is orthologous to murine RGMc (>85% amino acid identity). Due to the involvement of the mRGMc/HFE2 gene in the onset of these conditions, the generation of RGMc modified transgenic animals would aid in defining the biological role(s) of RGMc/HFE2, and produce an animal model of RGMc/HFE2 deficiency to be used in the design and assessment of chemical and biological approaches to modulating RGMc/HFE2 activity. Such RGMc modified transgenic animals can also be used as a valuable source of cells for cell culture experiments as well as high-throughput screening assays at the cellular level.